rs139294803

chr1-1048126-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):c.3866C>T(p.Pro1289Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,570,118 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1289S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (29 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.61

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003664583).
• BP6: Variant 1-1048126-C-T is Benign according to our data. Variant chr1-1048126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1048126-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00629 (958/152314) while in subpopulation AFR AF= 0.009 (374/41558). AF 95% confidence interval is 0.00825. There are 5 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.3866C>T	p.Pro1289Leu	missense_variant	23/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.3866C>T	p.Pro1289Leu	missense_variant	23/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.3551C>T	p.Pro1184Leu	missense_variant	22/38
AGRN	ENST00000652369.1	c.3551C>T	p.Pro1184Leu	missense_variant	22/35
AGRN	ENST00000620552.4	c.3452C>T	p.Pro1151Leu	missense_variant	23/39	5

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 956 AN: 152196 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00898

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00496 AC: 899 AN: 181330 Hom.: 1 AF XY: 0.00488 AC XY: 484 AN XY: 99256

Gnomad AFR exome AF: 0.00953

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000564

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00141

Gnomad NFE exome AF: 0.00779

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00596 AC: 8454 AN: 1417804 Hom.: 29 Cov.: 35 AF XY: 0.00587 AC XY: 4129 AN XY: 703066

Gnomad4 AFR exome AF: 0.00937

Gnomad4 AMR exome AF: 0.00308

Gnomad4 ASJ exome AF: 0.000821

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.00134

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.00629 AC: 958 AN: 152314 Hom.: 5 Cov.: 32 AF XY: 0.00607 AC XY: 452 AN XY: 74488

Gnomad4 AFR AF: 0.00900

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00695

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00676 Hom.: 3

Bravo AF: 0.00696

ESP6500AA AF: 0.00652 AC: 28

ESP6500EA AF: 0.00682 AC: 58

ExAC AF: 0.00439 AC: 518

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	AGRN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.35
Dann	Benign	0.66
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.29	N;.
REVEL	Benign	0.059
Sift	Benign	0.40	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.092
MVP		0.54
MPC		0.12
ClinPred		0.0028	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139294803; hg19: chr1-983506; COSMIC: COSV65070065; COSMIC: COSV65070065;